9-95173987-T-G

Variant names:

• chr9-95173987-T-G
• rs400727
• NM_000136.3:c.346-1840A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000136.3(FANCC):​c.346-1840A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 152,262 control chromosomes in the GnomAD database, including 61,950 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.90 (61950 hom., cov: 32)
• Consequence: FANCC NM_000136.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 6 publications found

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

FANCC Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• malignant pancreatic neoplasm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.346-1840A>C		intron_variant	Intron 4 of 14	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.346-1840A>C		intron_variant	Intron 4 of 14	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.901 AC: 137076 AN: 152144 Hom.: 61924 Cov.: 32

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.973

Gnomad AMR AF: 0.907

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.921

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.924

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.901 AC: 137156 AN: 152262 Hom.: 61950 Cov.: 32 AF XY: 0.900 AC XY: 67036 AN XY: 74444

African (AFR) AF: 0.824 AC: 34200 AN: 41526

American (AMR) AF: 0.907 AC: 13875 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 3399 AN: 3472

East Asian (EAS) AF: 0.908 AC: 4715 AN: 5190

South Asian (SAS) AF: 0.892 AC: 4298 AN: 4818

European-Finnish (FIN) AF: 0.921 AC: 9765 AN: 10604

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.937 AC: 63777 AN: 68032

Other (OTH) AF: 0.922 AC: 1952 AN: 2116

Alfa AF: 0.923 Hom.: 83634

Bravo AF: 0.897

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.9
DANN	Benign	0.84
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs400727; hg19: chr9-97936269;